Review articleA20: A multifunctional tool for regulating immunity and preventing disease
Section snippets
A20 and the Ub mediated regulation of cellular processes
Protein ubiquitination is a post-translational modification that orchestrates diverse cellular functions. The prevalence of intracellular ubiquitination events is expansive, and proteomic analyses reveal a large fraction of the mammalian genome is dedicated to encoding Ub associated and Ub interacting proteins [1], [2], [3]. Substrate proteins may be modified by the addition of a single Ub (monoubiquitination) by an enzyme complex that includes an E1 Ub activating enzyme, an E2 Ub conjugating
A20’s links to human disease
A20, or TNFAIP3, is a remarkably potent regulator of Ub dependent signals and of immune homeostasis. Among ubiquitination regulators, A20 has garnered increasing attention because of its multiple links to human disease [15], [16]. Initially, genome wide association studies (GWAS) linked single nucleotide polymorphisms (SNPs) in the A20 gene locus with the incidence of rheumatoid arthritis, systemic lupus erythematosus (SLE), psoriasis, rheumatoid arthritis, celiac disease, inflammatory bowel
A20 and adaptive immunity
Most cell types express baseline levels of A20 protein that is further induced by stimulation with a variety of ligands such as TNF that trigger NF-κB signaling. The induction of A20 expression by pro-inflammatory signals suggests A20 is a negative feedback regulator of inflammation. Spontaneous activation of multiple immune cell types was first observed in globally A20 deficient (A20−/−) mice, leading to multi-organ inflammation and perinatal death [46]. A20’s broad expression presented
A20 functions in innate immunity
Spontaneous inflammation, perinatal lethality, and enhanced NF-κB signaling are the most prominent phenotypes in A20−/− mice. These inflammatory phenotypes persist in A20−/− RAG-1−/− compound mutant mice, indicating that A20 performs critical physiological functions independently of adaptive lymphocytes [46]. T and B cell independent regulatory functions of A20 may broadly be partitioned into regulation of innate immune cells or non-hematopoietic cells. Potent inhibition of innate immune
Non-hematopoietic functions of A20
A20 expression is induced in non-hematopoietic cells as well as immune cells. The genetic association of A20 with a variety of distinct autoimmune diseases—including diseases afflicting specific tissues—prompted investigations of A20’s physiological functions in tissue restricted cell types such as intestinal, lung, and skin epithelial cells. A20 deficiency in villin-expressing intestinal epithelial cells (IECs) renders mice susceptible to dextran sulfate sodium (DSS) [69]. This defect also
A20 beyond NF-κB signaling
Lineage specific studies of A20 have not only highlighted diverse cell type specific functions for this protein, but have also expanded A20’s cell autonomous functions. While A20’s capacity to prevent inflammation has largely been ascribed to its ability to restrict NF-κB signaling, A20 also appears to regulate additional Ub dependent signals.
While cells with deficient NF-κB signals are more susceptible to programmed cell death, A20 deficient fibroblasts and T cells are more susceptible to cell
Biochemical mechanisms by which A20’s mediates its functions
While A20 clearly regulates ubiquitination of multiple signaling complexes, the precise biochemical mechanisms by which A20 performs these functions remain surprisingly enigmatic and complex. The A20 protein is a cysteine protease with de-ubiquitinating (DUB) activity [45], [57]. A20 also possesses seven zinc finger motifs that mediate binding to at least two types of polyubiqutin chains, RIP1, IKKγ, TRAF2, and a number of additional Ub dependent proteins (e.g., ABIN-1, RNF11, TAX1BP1). Hence,
Outstanding questions/future areas for discovery
If A20 performs critical non-catalytic functions, then A20 may partly function as an adaptor and/or scaffold protein. This function could involve some of A20’s binding partners, several of which display overlapping signaling functions with A20. For example, ABIN-1 and TAX1BP1 share A20’s ability to restrict TNF and TLR induced NF-κB responses as well as TNF induced cell death [81], [82], [83], [84], [85]. A20 would be an unusual adaptor protein, as it is dynamically regulated at transcriptional
Acknowledgements
We apologize to contributors in this field that we have not had room to reference.
Work from the authors’ laboratory was supported by NIH R01 grants AI117908, DK095693, and AI35198.
References (88)
- et al.
Systematic and quantitative assessment of the ubiquitin-modified proteome
Mol. Cell
(2011) - et al.
Quantifying ubiquitin signaling
Mol. Cell
(2015) - et al.
Polyubiquitin chains: polymeric protein signals
Curr. Opin. Chem. Biol.
(2004) - et al.
Ubiquitin code assembly and disassembly
Curr. Biol.
(2014) - et al.
Direct, noncatalytic mechanism of IKK inhibition by A20
Mol. Cell
(2011) - et al.
Regulation of NF-κB by ubiquitination
Curr. Opin. Immunol.
(2013) - et al.
Mixed-linkage ubiquitin chains send mixed messages
Structure
(2013) - et al.
Lys63/Met1-hybrid ubiquitin chains are commonly formed during the activation of innate immune signalling
Biochem. Biophys. Res. Commun.
(2016) - et al.
Heterotypic ubiquitin chains: seeing is believing
Trends Cell Biol.
(2018) - et al.
Ubiquitin makes its mark on immune regulation
Immunity
(2010)